1. Field of the Invention
The invention relates to a pharmaceutical composition for oral application and to a method of preparing thereof.
2. Description of the Related Art
Pharmaceutical drugs often have certain desirable properties but an undesirable smell and/or taste. These properties have a great impact on patient compliance and marketing of the pharmaceutical product. This is especially true for animals having an extremely well-developed sense of taste and smell.
In general drug delivery systems for taste masking can be achieved by either chemically or physically modifying a drug powder. The latter option is more interesting since toxicological investigations of the new compound can be avoided.
In general physical taste masking technologies rely on preventing interaction between the drug molecule and the oral mucosal surface and various approaches and several manufacturing processes for masking the unpleasant taste of drugs as solid dosage forms have been proposed. These include barrier methods (embedding, coating, encapsulation), use of flavours and sweeteners and complexation and adsorption approaches. Thus taste masked powders are formed by methods known of the art such as spray drying, granulation and coacervation. A review is given, for example, in SUN et al. (American Pharmaceutical Review, 16-28, 1999).
For complexation, adsorption and inclusion of bad-tasting drugs ion-exchange resins, ionic polymers (acrylic acid-/cellulose-derivates, chitosan), cyclodextrins and other additives such as phospholipids or tannic acid have been used.
Taste-masking of ionic drugs can be achieved using materials containing basic or acidic groups that interact with the ionisable molecule thus creating insoluble salts. Since bitter drugs in non-dissolved state have no taste the idea is that the drug is not dissolved, i.e. released, during passage through the mouth. Nature and extend of the interaction between the drug and the additive depend on factors such as pK of the drug and the additive, ionic strength, pH of the fluid, solubility of the drug and chemical structure of the additive.
Thus Prabhu, N. (Indian Journal of Pharmaceutical Sciences, May-June 2002) described taste masking of clarithromycin by complexation with tannic acid.
U.S. Pat. No. 5,219,563 (Douglas, S. J., 1990) and U.S. Pat. No. 3,594,470 (Borodkin, S. and Sundberg, D. P., 1971) provide methods of taste-masking by loading the anionic drug onto a methacrylic acid/divinylbenzene copolymer (Amberlite®).
U.S. Pat. No. 3,974,272 (Polli, G. P. and Shoop, C. E., 1976) provide a method for a palatable cholestyramine coacervate by loading a cationic drug onto a styrene/divinylbenzene copolymer (Duolite®).
U.S. Pat. No. 5,560,921 (Damani, N. C. and Viehues, R., 1995) and U.S. Pat. No. 4,971,791 (Tsau, J. H. and Damani, N. C, 1990) provide a method of taste-masking by complexing the drug with a polymethacrylate polymer.
More complicated is the taste-masking of neutral drugs by complexation/adsorption as can be deduced form the number patent applications.
Carbohydrates e.g. can entrap hydrophobic/lipophilic drugs. Most commonly taste-masking is achieved by inclusion of the bitter drug in cyclodextrin cavities, where the binding of the bitter guest molecule within the host cyclodextrin is not fixed or permanent but a dynamic equilibrium (Szejtli, J., Medicinal Research Review, 14(3): 353-386, 1994).
U.S. Pat. No. 5,681,577 (Lech, S., Schobel, A. M. and Denick, J., 1995) provides a different approach and a method of taste-masking by adsorbing the drug (pseudoephedrine, dextromethorphan, diphenhydramine) to silicon dioxide, U.S. Pat. No. 4,647,459 (Peters, D., Denick, J. and Talwar, A. K.) uses magnesium trisilicate for adsorption.
Charcoal is well-know and commonly used to prevent absorption of drugs from the gastrointestinal tract in case of intoxication by adsorbing them. Charcoal is also used for blood purification in hemoperfusion. A less common effect used in medicine is the adsorption effect of charcoal on Escherichia coli or aflatoxin. The indications mentioned above are only dealing with the adsorption effect of charcoal.
Some investigators however have taken into consideration that, as in cyclodextrins, adsorption is not a one-way process but there is also some desorption of a drug from charcoal. They are using charcoal as excipent for sustaining the release of a drug in the gastrointestinal tract (e.g. Roivas, L. et al., Methods Find Exp Clin Pharmacol, 16(2):125-32, 1994). However, sustained release of a drug from an excipient does not automatically lead to the assumption that the excipient may be advantageously used for taste masking of a drug.
Up to now taste-masked particles produced by the methods mentioned above often suffer from problems such as:                Only drugs can be used that either have cationic functionality (e.g. —COOH or Na/K salts) or anionic functionality (e.g. —NH2, HCl salts etc.);        The taste barrier is physically damaged during further processing of the drug to the finished product, e.g. by the tabletting process;        The barrier is physically damaged during ingestion by chewing on it. This happens when the particles are too big because only particles smaller than 50 μm (the distance between taste buds in the mouth) don't give a sandy mouth feel. This demand is challenging because smaller particles have a larger surface area-to-volume ratio and dissolve more rapidly in the mouth than larger particles;        Maintaing acceptable sensory attributes cannot be achieved while achieving acceptable bioavailability. This is especially problematic in the case of low-soluble drugs such as those of BCS system class II and IV.        One possible problem is that the complexation force is too strong leading to a sustained release of the drug.        Another possible problem is that some pharmaceutical compositions are using the concept that, at the pH in the mouth (approximetly 5.9-7.8), the drug remains insoluble. However this is also the pH which can be found in the intestinal tract and where the drug has to be dissolved because absorption takes place;        Commonly used complexing or coating agents are soluble or somewhat permeable at the pH of the saliva. E.g. Eudragit L (methacrylic acid copolymer A) is soluble from pH 5.5, Eudragit S (methacrylic acid copolymer) is soluble from pH 7;        The threshold concentration for bitter taste of the drug is very low;        The drug to be coated has an unfavourable crystal form, e.g. in the case of praziquantel a needle;        The technologies involved are rather sophisticted i.e. solvents are used or risky technologies such as nano particle systems, several steps are necessary during production and/or special equipment;        
Moreover, S. T. Hong et al., Parasitol Res., Oct. 1, 2003; 91(4): 316-20 further describes that it is desirable to apply an anthelmintic drug in a sustained release form using hydroxypropylmethylcellulose as carrier. Not only because plasma concentrations are short due to their rapid absorption and secretion after ingestion but also because some of them are mainly acting by direct contact with the parasite in the gastrointestinal tract making it desirable that the dose remains in the gastrointestinal tract for a longer time. As starch and cellulose are soluble and swellable, respectively, in water i.e. in the spittle, taste-masking of the drug is not at all sufficient.